Cancers remain the cause of poor health and early death throughout the world. Despite advances in treatment, cancer remains the second leading cause of death in the United States and is the leading cause of death in 21 states as of 2016. Further, the probability of being diagnosed with an invasive cancer was found to be 42% for men and 37.6% for women living in the United States according to a study by Siegel and others (“Cancer statistics, 2016,” CA Cancer J Clin, vol. 66, no. 1, pp. 7-30, 2016 January-February 2016). The same study reported that 582,623 deaths in 2012 were a result of cancer and projected that 1,685,210 new cancer cases and 595,690 cancer deaths would occur during 2016.
Treatment of cancers has traditionally been accomplished through one of, or a combination of, chemotherapy, surgery, radiotherapy, immunotherapy, and hormone therapy, among others. Unfortunately, differences in genetic expression, drug sensitivity, cell morphology, and metastatic targets across the dozens of known cancer types has stymied the long-term success of treatments. Acquired drug resistance in response to chemotherapy remains another hurdle in cancer treatment that demands a diverse arsenal of cytotoxic agents. Cancer recurrence and distant metastases, potentially explained by inherently robust and drug resistant cancer stem cells, further hinder positive prognoses in cancer patients. It is hypothesized that cancer stem cells can remain dormant and undetected in the body for years before reactivating and beginning the formation of a new tumor. As such, cancer recurrence and distant metastases continue to plague cancer patients after months or even years of remission using current treatments.
The role of immune cells in combatting aggressive tumors has become increasingly recognized in the medical community and has led to new approaches for cancer therapies. FDA approval of the first therapeutic cancer vaccine, sipuleucel-T, and other cancer immunotherapy drugs, including monoclonal antibodies such as ipilimumab, in addition to increased understanding of the immune system's role in the tumor microenvironment, has led to a call for small molecules capable of regulating immune activity and supporting tumor death.
In spite of such advances, many shortcomings and disadvantages of current chemotherapeutics and other cancer treatments are readily apparent. The hair loss, nausea, vomiting, loss of appetite, compromised immune system, and other side effects commonly associated with a cancer therapy are often a consequence of the currently utilized treatments and not the disease itself.
Unfortunately, a push to develop chemotherapeutic drugs capable of targeting a specific molecule or cancer-associated signaling pathway with reduction in side effects has failed to yield the expected improvements in patient prognoses. This is largely due to the ability of cancer cells to utilize a combination of many different cellular mechanisms to enhance viability. In many cases, cancer cells are able to circumvent apoptosis induced from targeted therapies by simply activating other survival pathways after the initial treatment.
Natural products are a historically successful source of medicinally active compounds with fewer unwanted side effects, especially in regard to chemotherapeutics. In fact, 63% of cancer drugs used between 1981 and 2006 were natural products, were inspired by natural products, or were synthesized from a natural pharmacophore. Medicinally active compounds derived from natural materials have the potential to provide targeted cytotoxic and immune modulating responses while limiting the taxing side effects associated with currently utilized cancer treatments. The use of natural products attempts to balance a robust ability to target numerous pathways simultaneously with a historical record of safe human consumption and benign side effects.
There is a need to discover and optimize the use of novel cytotoxic compounds with low IC50 values, diverse biological targets, immune regulatory capability, and diminished side effects. In addition, there is a need for new treatments engineered to target pathogenic cells both during initial treatment of cancers and after remission has occurred in order to prevent cancer recurrence. New treatments based upon natural materials that can provide efficacy with benign or limited side effects would be of great benefit.